CN114106227A - Preparation method of structured hydrogel and hydrogel heart and valve - Google Patents

Preparation method of structured hydrogel and hydrogel heart and valve Download PDF

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Publication number
CN114106227A
CN114106227A CN202111591052.7A CN202111591052A CN114106227A CN 114106227 A CN114106227 A CN 114106227A CN 202111591052 A CN202111591052 A CN 202111591052A CN 114106227 A CN114106227 A CN 114106227A
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hydrogel
water
monomer
printing
ink
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CN114106227B (en
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王晓龙
吴家宇
蒋盼
鲁耀钟
周峰
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Lanzhou Institute of Chemical Physics LICP of CAS
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Lanzhou Institute of Chemical Physics LICP of CAS
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Priority to PCT/CN2022/117682 priority patent/WO2023116060A1/en
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F120/52—Amides or imides
    • C08F120/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F120/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
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    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/30—Auxiliary operations or equipment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
    • B33Y40/20—Post-treatment, e.g. curing, coating or polishing
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    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B33Y70/10—Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
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    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
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    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
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Abstract

The invention belongs to the technical field of hydrogel, and provides a method for preparing structured hydrogel and hydrogel heart and valve. The preparation method comprises the following steps: providing a photo-curable hydrogel ink; establishing a three-dimensional model, and carrying out photocuring 3D printing on the photocuring hydrogel ink to obtain printed hydrogel; carrying out water immersion on the printing hydrogel to obtain the structural functional hydrogel; the photo-curable hydrogel ink includes: high-density hydrogen bond type unsaturated monomers, photoinitiators, dyes and solvents; the solvent includes water and dimethyl sulfoxide. According to the invention, a high-density hydrogen bond type unsaturated monomer is dissolved in a mixed solvent of dimethyl sulfoxide and water to prepare the photocuring hydrogel ink, and after photocuring 3D printing is carried out, the obtained printing hydrogel is soaked in water, so that the dimethyl sulfoxide in the printing hydrogel is diffused into the water to carry out phase inversion, and thus hydrogen bonds in the printing hydrogel are reconstructed, and finally the toughness of the structural functional hydrogel is improved.

Description

Preparation method of structured hydrogel and hydrogel heart and valve
Technical Field
The invention relates to the technical field of hydrogel, in particular to a method for preparing structured hydrogel and hydrogel heart and valve.
Background
In recent years, novel biomaterials such as polymers, ceramics, metals and the like have been rapidly developed and widely used in the medical field, and the treatment efficiency of a plurality of diseases is greatly improved. Although biomaterials are very widely used in biomedicine, many biomaterials are still limited in their application due to their lack of desirable functional properties (e.g., biomechanical matching, biocompatibility, personalized biomanufacturing, and surface-interface interactions in biological systems).
Based on the present state of the art and future developments in biomaterials, there is a need to control the design, synthesis, function and structured fabrication of new biomaterials, thereby creating new biomaterials based on hydrogels. Hydrogels have a hydrophilic polymer network structure, and water can penetrate between the polymer chains of the hydrophilic polymer network structure, resulting in swelling. The advantages of hydrogels in biological applications are their high moisture content, biomechanical compatibility and biocompatibility. Conventional hydrogels are generally classified into two broad categories, natural hydrogels and synthetic hydrogels. The natural hydrogel comprises polysaccharides (such as cellulose, alginic acid, hyaluronic acid, chitosan, etc.) and polypeptides (such as poly-L-lysine, collagen, poly-L-glutamic acid, etc.). Synthetic hydrogels include alcohols, acrylic acids and their derivatives (e.g., polyacrylic acid, polymethacrylic acid, polyacrylamide, etc.).
The existing hydrogel, whether natural hydrogel or synthetic hydrogel, has poor toughness.
Disclosure of Invention
In view of the above, the present invention is directed to a structured hydrogel and a method for making hydrogel heart and valves. The structured hydrogel obtained by the preparation method provided by the invention has excellent toughness.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a structured hydrogel, which comprises the following steps:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model to obtain printed hydrogel;
water leaching the printed hydrogel to obtain the structured hydrogel;
the photo-curable hydrogel ink comprises the following components: monomers, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea;
the solvent includes water and dimethyl sulfoxide.
Preferably, the monomer further comprises a low density hydrogen bond type unsaturated monomer, and the low density hydrogen bond type unsaturated monomer comprises acrylamide or acrylic acid.
Preferably, the mass ratio of water to dimethyl sulfoxide in the solvent is 9: 1-1: 9.
preferably, the photoinitiator is an aqueous photoinitiator; the aqueous photoinitiator comprises one or more of a 2959 photoinitiator, a LAP photoinitiator, and a V-50 photoinitiator; the mass of the photoinitiator is 0.1-1% of the mass of the monomer.
Preferably, the mass percentage of the solute in the photo-curing hydrogel ink is 5-30%.
Preferably, the parameters of the photocuring 3D printing include: the wavelength of the light source is 385-405 nm; the exposure time of each layer is 5 s-60 s; the thickness of the slicing layer is 0.05 mm-0.1 mm.
Preferably, the water immersion time is 5-15 days.
The invention also provides a preparation method of the hydrogel heart and the hydrogel valve, which comprises the following steps:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model of the heart and the valve to obtain printed hydrogel;
water leaching the printed hydrogel to obtain the structured hydrogel;
mixing the structured hydrogel and functional monomers, and carrying out surface modification to obtain the hydrogel heart and valve;
the photo-curable hydrogel ink comprises the following components: monomers, RAFT reagents, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea;
the solvent comprises water and dimethyl sulfoxide;
the functional monomer comprises sodium styrene sulfonate or a heparinoid type active monomer.
Preferably, the RAFT agent is a water soluble RAFT agent; the water soluble RAFT agent comprises 4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid, 2- (n-butyl thiocarbonylthio) propanoic acid or 4-cyano-4- ((dodecylsulfanylthiocarbonyl) sulfanyl) pentanoic acid; the mass of the RAFT reagent is 0.1-2% of the mass of the monomer.
Preferably, the temperature of the surface modification is 60-90 ℃, and the time is 5 min-48 h.
The invention provides a preparation method of a structured hydrogel, which comprises the following steps: providing a photo-curable hydrogel ink; carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model to obtain printed hydrogel; water leaching the printed hydrogel to obtain the structured hydrogel; the photo-curable hydrogel ink comprises the following components: monomers, photoinitiators, dyes and solvents; the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea; the solvent includes water and dimethyl sulfoxide. According to the invention, a high-density hydrogen bond type unsaturated monomer is dissolved in a mixed solvent of dimethyl sulfoxide and water to prepare the photocuring hydrogel ink, and after photocuring 3D printing is carried out, the obtained printing hydrogel is soaked in water, so that the dimethyl sulfoxide in the printing hydrogel is diffused into the water to carry out phase inversion, and thus hydrogen bonds in the printing hydrogel are reconstructed, and finally the toughness of the structural functional hydrogel is improved.
The invention also provides a preparation method of the hydrogel heart and the hydrogel valve, which comprises the following steps: providing a photo-curable hydrogel ink; carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model of the heart and the valve to obtain printed hydrogel; water leaching the printed hydrogel to obtain the structured hydrogel; mixing the structured hydrogel and functional monomers, and carrying out surface modification to obtain the hydrogel heart and valve; the photo-curable hydrogel ink comprises the following components: monomers, RAFT reagents, photoinitiators, dyes and solvents; the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea; the solvent comprises water and dimethyl sulfoxide; the functional monomer comprises sodium styrene sulfonate or a heparinoid type active monomer. According to the invention, a high-density hydrogen bond type unsaturated monomer is dissolved in a mixed solvent of dimethyl sulfoxide and water to prepare the photocuring hydrogel ink, and after photocuring 3D printing is carried out, the obtained printing hydrogel is soaked in water, so that the dimethyl sulfoxide in the printing hydrogel is diffused into the water to carry out phase inversion, and thus hydrogen bonds in the printing hydrogel are reconstructed, and finally the toughness of the structural functional hydrogel is improved. And then the surface modification is carried out on the structured hydrogel by using sodium styrene sulfonate or a heparinoid type active monomer, so that the cell compatibility, the blood compatibility and the tissue compatibility of hydrogel hearts and valves can be improved.
Drawings
FIG. 1 is a schematic diagram illustrating the preparation of a structured hydrogel according to the present invention;
FIG. 2 is an optical photograph of the structured hydrogel prepared in example 1;
FIG. 3 is a graph of the mechanical properties of the structured hydrogel prepared in example 1;
FIG. 4 is a graph of the mechanical properties of the structured hydrogel prepared in example 2;
FIG. 5 is a graph of the mechanical properties of the structured hydrogel prepared in example 3;
FIG. 6 is a graph of the mechanical properties of the structured hydrogel prepared in example 3;
FIG. 7 is an optical photograph of the resulting structured hydrogel prepared in example 5;
FIG. 8 is a graph of the mechanical properties of the structured hydrogel prepared in example 5;
FIG. 9 is a graph of the mechanical properties of the structured hydrogel prepared in comparative example 1;
FIG. 10 is an optical photograph of the hydrogel heart valve prepared in example 7;
FIG. 11 is a graph of the mechanical properties of the hydrogel heart valve prepared in example 7;
FIG. 12 is an optical photograph of the tubular hydrogel heart valve prepared in example 8;
FIG. 13 is an optical photograph of the heart prepared in example 8;
FIG. 14 is a graph of the mechanical properties of the hydrogel heart valve prepared in example 9;
FIG. 15 is a graph of the mechanical properties of the hydrogel heart valve prepared in example 10;
FIG. 16 is an optical photograph of the hydrogel heart valve prepared in example 11;
FIG. 17 is a graph of the mechanical properties of the hydrogel heart valve prepared in comparative example 4;
fig. 18 is a graph of the mechanical properties of the hydrogel heart valve prepared in comparative example 5.
Detailed Description
The invention provides a preparation method of a structural functional hydrogel, which comprises the following steps:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model to obtain printed hydrogel;
carrying out water immersion on the printing hydrogel to obtain the structural functional hydrogel;
the photo-curable hydrogel ink comprises the following components: monomers, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer comprising N-acryloyl semicarbazide (C)4H7N3O2NASC), N-acryloyl glycinamide (C)5H8N2O2One or more of NAGA), allylurea and propyleneurea;
the solvent includes water and dimethyl sulfoxide.
In the present invention, the starting materials used in the present invention are preferably commercially available products unless otherwise specified.
The present invention provides a photo-curable hydrogel ink.
In the present invention, the photo-curable hydrogel ink includes the following components: monomers, photoinitiators, dyes and solvents.
In the present invention, the monomer includes a high-density hydrogen bond type unsaturated monomer; the high-density hydrogen bond type unsaturated monomer includes N-acryloyl semicarbazide (C)4H7N3O2NASC), N-acryloyl glycinamide (C)5H8N2O2NAGA), allyl urea and allyl urea, preferably N-acryloyl semicarbazide or N-acryloyl glycinamide, and more preferablyOptionally including N-acryloyl semicarbazide.
In the present invention, the monomer preferably further includes a low-density hydrogen bond type unsaturated monomer; the low-density hydrogen bond type unsaturated monomer preferably includes acrylamide or acrylic acid. In the present invention, the mass ratio of the low-density hydrogen bond type unsaturated monomer to the high-density hydrogen bond type unsaturated monomer is preferably (1 to 5): more preferably (2-4): 10.
in the present invention, the photoinitiator is preferably an aqueous photoinitiator; the aqueous photoinitiator preferably comprises one or more of photoinitiator 2959, photoinitiator LAP, and photoinitiator V-50. In the present invention, the mass of the photoinitiator is preferably 0.1 to 1%, preferably 0.5% of the mass of the monomer.
In the present invention, the dye is preferably an aqueous dye, and the aqueous dye preferably includes lemon yellow or anthocyanin. In the invention, the mass of the dye is preferably 0.02-0.5% of the mass of the monomer.
In the present invention, the solvent includes water and dimethyl sulfoxide. In the invention, the mass ratio of water to dimethyl sulfoxide in the solvent is 9: 1-1: 9, more preferably 7: 3.
in the invention, the mass percentage of solute in the photocuring hydrogel ink is preferably 5-30%; the solute refers to all components of the photocurable hydrogel ink except the solvent.
After the photocuring hydrogel ink is provided, the photocuring hydrogel ink is subjected to 3D printing according to a preset three-dimensional model, so that the printed hydrogel is obtained.
In the present invention, the parameters of the 3D printing include: the wavelength of the light source is preferably 385-405 nm, and more preferably 405 nm; the exposure time of each layer is preferably 5-60 s, and more preferably 20-30 s; the thickness of the slicing layer is preferably 0.05 mm-0.1 mm; the temperature of the printing environment is preferably room temperature, i.e. neither additional cooling nor additional heating is required.
After the printing hydrogel is obtained, the printing hydrogel is soaked in water to obtain the structured hydrogel.
In the present invention, the time for the water immersion is preferably 5 to 15 days, and more preferably 10 days. In the present invention, the temperature of the water immersion is preferably room temperature, i.e., neither additional cooling nor additional heating is required. In the present invention, the water immersion means that the printed hydrogel is soaked in water to perform phase inversion.
FIG. 1 is a schematic diagram of the preparation of the structural functional hydrogel provided by the present invention.
The invention also provides a preparation method of the hydrogel heart and the hydrogel valve, which comprises the following steps:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model of the heart and the valve to obtain printed hydrogel;
soaking the printed hydrogel in water to obtain a structured hydrogel;
mixing the structured hydrogel and functional monomers, and carrying out surface modification to obtain the hydrogel heart and valve;
the photo-curable hydrogel ink includes the following: monomers, RAFT reagents, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer comprising N-acryloyl semicarbazide (C)4H7N3O2NASC), N-acryloyl glycinamide (C)5H8N2O2One or more of NAGA), allylurea and propyleneurea;
the solvent comprises water and dimethyl sulfoxide;
the functional monomer comprises sodium styrene sulfonate or a heparinoid type active monomer.
The present invention provides a photo-curable hydrogel ink.
In the present invention, the photo-curable hydrogel ink includes the following: monomers, RAFT agents, photoinitiators, dyes and solvents.
In the present invention, the monomer includes a high-density hydrogen bond type unsaturated monomer; the high density hydrogen bondsThe unsaturated monomer includes N-acryloyl semicarbazide (C)4H7N3O2NASC), N-acryloyl glycinamide (C)5H8N2O2NAGA), allyl urea and acryl urea, preferably comprising N-acryloyl semicarbazide or N-acryloyl glycinamide, and further preferably comprising N-acryloyl semicarbazide.
In the present invention, the monomer preferably further includes a low-density hydrogen bond type unsaturated monomer; the low-density hydrogen bond type unsaturated monomer preferably includes acrylamide or acrylic acid. In the present invention, the mass ratio of the low-density hydrogen bond type unsaturated monomer to the high-density hydrogen bond type unsaturated monomer is preferably (1 to 5): more preferably (2-4): 10.
in the present invention, the RAFT agent is preferably a water-soluble RAFT agent; the water soluble RAFT agent preferably comprises 4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid, 2- (n-butyl thiocarbonylthio) propanoic acid or 4-cyano-4- ((dodecylsulfanylthiocarbonyl) sulfanyl) pentanoic acid. In the present invention, the mass of the RAFT agent is preferably 0.1 to 2% of the mass of the monomer.
In the present invention, the photoinitiator is preferably an aqueous photoinitiator; the aqueous photoinitiator preferably comprises one or more of photoinitiator 2959, photoinitiator LAP, and photoinitiator V-50. In the present invention, the mass of the photoinitiator is preferably 0.1 to 1%, preferably 0.5% of the mass of the monomer.
In the present invention, the dye is preferably an aqueous dye; the aqueous dye preferably comprises lemon yellow, eosin or anthocyanidin. In the invention, the mass of the dye is preferably 0.02-0.5% of the mass of the monomer.
In the present invention, the solvent includes water and dimethyl sulfoxide. In the invention, the mass ratio of water to dimethyl sulfoxide in the solvent is 9: 1-1: 9, more preferably 7: 3.
in the invention, the mass percentage of solute in the photocuring hydrogel ink is preferably 5-40%; the solute refers to all components of the photocurable hydrogel ink except the solvent.
After providing the photo-curing hydrogel ink, the photo-curing 3D printing is carried out on the photo-curing hydrogel ink according to the preset three-dimensional model of the heart and the valve, and the printing hydrogel is obtained.
In the present invention, the parameters of the photocuring 3D printing include: the wavelength of the light source is preferably 385-405 nm, and more preferably 405 nm; the exposure time of each layer is preferably 5s to 60s, and more preferably 20s to 30 s; the thickness of the slicing layer is preferably 0.05 mm-0.1 mm; the temperature of the printing environment is preferably room temperature, i.e. neither additional cooling nor additional heating is required.
After the printing hydrogel is obtained, the printing hydrogel is soaked in water to obtain the structured hydrogel.
In the invention, the water immersion time is preferably 5-15 days. In the present invention, the temperature of the water immersion is preferably room temperature, i.e., neither additional cooling nor additional heating is required. In the present invention, the water immersion means that the printed hydrogel is soaked in water to perform phase inversion.
After obtaining the structured hydrogel, mixing the structured hydrogel with a functional monomer, and carrying out surface modification to obtain the hydrogel heart and valve; the functional monomer comprises sodium styrene sulfonate or a heparinoid type active monomer.
In the present invention, the functional monomer includes sodium styrene sulfonate or a heparinoid type active monomer.
In the present invention, the functional monomer is preferably used in the form of a functional monomer solution, and the solvent of the functional monomer solution is preferably a polar solvent, and the polar solvent preferably includes water, N-dimethylformamide, N-dimethylacetamide, or tetrahydrofuran; the mass concentration of the functional monomer solution is 5-80%.
In the invention, the temperature of the surface modification is preferably 60-90 ℃, and more preferably 70-80 ℃; the time for the surface modification is preferably 5min to 48 h.
After the surface modification, the invention preferably further comprises the step of placing the obtained surface modification system in water for balancing to obtain the hydrogel heart and valve.
In the present invention, the temperature of the equilibrium is preferably room temperature, i.e. neither additional heating nor additional cooling is required. In the present invention, the time for the equilibration is preferably 12 to 72 hours.
The following examples are provided to illustrate the method for preparing the structured hydrogel and the method for preparing the hydrogel heart and valve, but they should not be construed as limiting the scope of the present invention.
Example 1
Adding 15.000g of N-acryloyl semicarbazide into 35.000g of a mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of the dimethyl sulfoxide to the deionized water is 7: 3), adding 0.075g of photoinitiator (LAP) (0.5 percent of the mass of the monomer) after the monomer is completely dissolved, and adding 0.010g of lemon yellow to finally obtain uniform and transparent photocuring hydrogel ink.
Transferring the photo-curing hydrogel ink into a material box of a photo-curing 3D printer, wherein the light source of the printer is 405nm, the exposure time of each layer is 20-30 s, the thickness of each layer is 0.1mm, and the temperature of a printing environment is room temperature; and establishing a model by using three-dimensional modeling software, and importing 3D printing software to drive printer manufacturing. The printed hydrogel was soaked in deionized water for 10 days to obtain a structured hydrogel, and an optical photograph of the obtained structured hydrogel is shown in fig. 2.
The mechanical properties of the structured hydrogel were tested using a universal material testing machine, and the test results are shown in fig. 3. As can be seen from fig. 3: the tensile strength of the structured hydrogel reaches 4.43 +/-0.74 MPa when the strain is 70 +/-53 percent, the elastic modulus is 62.61 +/-12.87 MPa according to the calculation of a stress-strain curve, and the tearing energy of the structured hydrogel is 21.35 +/-0.24 kJ/m2。
Example 2
The differences from example 1 are: 10.000g of N-acryloyl semicarbazide and 5.000g of acrylamide were added. The mechanical properties of the structured hydrogel were measured by a universal material tester, and the results are shown in FIG. 4. As can be seen from FIG. 4, when the strain is 335. + -. 63%, the knot appearsThe tensile strength of the structured hydrogel reaches 2.51 +/-0.32 MPa, the elastic modulus is 2.90 +/-0.14 MPa according to the calculation of a stress-strain curve, and the tearing energy of the structured hydrogel is 17.25 +/-0.37 kJ/m2。
Example 3
8.330g of N-acryloyl semicarbazide and 4.170g of acrylamide are added into 37.500g of mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of the dimethyl sulfoxide to the deionized water is 7: 3), 0.063g of initiator (LAP) (0.5 percent of the mass of the monomer) is added after the monomer is completely dissolved, and 0.01g of lemon yellow is added, so that uniform and transparent photo-curing hydrogel ink is finally obtained.
Printing and post-processing were the same as in example 1.
The mechanical properties of the structured hydrogel were tested using a universal material testing machine, and the test results are shown in fig. 5 and 6. As can be seen from fig. 5: when the strain is 410 +/-34%, the tensile strength of the structured hydrogel reaches 2.06 +/-0.20 MPa, and the elastic modulus is 1.06 +/-0.13 MPa calculated from a stress-strain curve. As can be seen in FIG. 6, the tear energy of the resulting structured hydrogel was 19.55. + -. 0.51kJ/m2。
Example 4
10.000g of N-acryloyl semicarbazide and 2.500g of acrylamide are added into 37.500g of mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of the dimethyl sulfoxide to the deionized water is 7: 3), 0.063g of initiator (LAP) (0.5 percent of the mass of the monomer) is added after the simple substance is completely dissolved, and 0.010g of lemon yellow is added, so that the uniform and transparent photo-curing hydrogel ink is finally obtained.
Printing and post-processing were the same as in example 1.
The mechanical property of the structured hydrogel is tested by using a universal material testing machine, when the strain is 557 +/-31%, the tensile strength of the structured hydrogel reaches 3.25 +/-0.37 MPa, the elastic modulus is 1.93 +/-0.22 MPa according to the stress-strain curve calculation, and the tearing energy of the structured hydrogel is 26.35 +/-0.27 kJ/m2。
Example 5
9.615g of N-acryloyl semicarbazide and 2.885g of acrylic acid are added into 37.500g of mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of the dimethyl sulfoxide to the deionized water is 7: 3), 0.063g of initiator (LAP) (0.5 percent of the mass of the monomer) is added after the simple substance is completely dissolved, and 0.010g of lemon yellow is added, so that the uniform and transparent photo-curing hydrogel ink is obtained. An optical photograph of the resulting structured functional hydrogel is shown in FIG. 7.
The mechanical properties of the structured hydrogel were tested using a universal material testing machine, and the test results are shown in fig. 8. As can be seen from fig. 8: when the strain is 572 +/-55%, the tensile strength of the structured hydrogel reaches 7.24 +/-0.47 MPa, the elastic modulus is 0.92MPa according to the calculation of a stress-strain curve, and the tearing energy of the structured hydrogel is 171.10 +/-34 kJ/m2。
Example 6
The differences from example 5 are: 9.615g of N-acryloylglycinamide and 2.885g of N-acryloylglycinamide are added.
Printing and post-processing were the same as in example 1.
The mechanical property of the structured hydrogel is tested by using a universal material testing machine, when the strain is 407 +/-28%, the tensile strength of the structured hydrogel reaches 1.82 +/-0.23 MPa, the elastic modulus is 0.65MPa according to the stress-strain curve calculation, and the tearing energy of the structured hydrogel is 18.45 +/-0.46 kJ/m2。
Comparative example 1
The N-acryloyl semicarbazide in example 1 was replaced with acrylamide.
The mechanical properties of the structured hydrogel were tested using a universal material testing machine, and the test results are shown in fig. 9. As can be seen from fig. 9: the tensile strength of the structured hydrogel reaches 2.51 +/-0.02 kPa when the strain is 124 +/-31 percent; the elastic modulus is calculated to be 3.87 +/-1.5 kPa according to the stress-strain curve; the tear energy of the structured hydrogel was 0.45. + -. 0.03kJ/m2。
Comparative example 2
Dimethyl sulfoxide was omitted from example 1.
Testing the mechanical property of the structured hydrogel by using a universal material testing machine, wherein when the strain is 212 +/-34 percent, the tensile strength of the structured hydrogel isThe tensile strength reaches 0.77 +/-0.11 MPa; the elastic modulus is calculated by a stress-strain curve and is 0.34 +/-0.02 MPa; tear energy of the structured hydrogel was 3.27. + -. 0.26kJ/m2。
Comparative example 3
The difference from example 1 is that no water immersion was carried out.
Testing the mechanical property of the obtained printing hydrogel by using a universal material testing machine, wherein the tensile strength of the printing hydrogel reaches 0.67 +/-0.08 MPa when the strain is 277 +/-28%; the elastic modulus is 0.39 plus or minus 0.21MPa and the tearing energy of the printed hydrogel is 2.77 plus or minus 0.31kJ/m calculated by a stress-strain curve2。
Example 7
8.3300g of N-acryloyl semicarbazide and 4.1700g of acrylamide were added to 37.5000g of a mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of dimethyl sulfoxide to water was 7: 3), 0.0625g of an initiator (LAP) (0.5% of the mass of the monomer) was added after the monomer was completely dissolved, 0.0125g of RAFT reagent (4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid) (0.1% of the mass of the monomer) was added, and 0.0100g of lemon yellow was added to finally obtain a uniform and transparent photocurable hydrogel ink.
Transferring the photo-curing hydrogel ink into a material box of a photo-curing 3D printer, wherein the light source of the printer is 405nm, the exposure time of each layer is 20-30 s, the thickness of each layer is 0.1mm, and the temperature of a printing environment is room temperature; and establishing a heart valve model by using three-dimensional modeling software, and importing 3D printing software to drive a printer to manufacture. Soaking the 3D-printed valve structure hydrogel with deionized water for 10 days to obtain a structured hydrogel heart valve;
soaking the structured hydrogel heart valve into sodium p-styrenesulfonate monomer solution (wherein the sodium p-styrenesulfonate is 10g, and the solvent is 90mL of N, N-dimethylformamide) for surface modification, and reacting for 1 hour at 60 ℃ under the protection of nitrogen;
and infiltrating the surface functionalized hydrogel heart valve into deionized water for 24 hours, and removing the N, N-dimethylformamide solvent to obtain the hydrogel heart valve (the specific structure is shown in figure 10).
The mechanical properties of the hydrogel heart valve are tested by using a universal material testing machine, the test result is shown in fig. 11, and as can be seen from fig. 11, when the strain is 475% + -82, the tensile strength of the hydrogel heart valve reaches 1.83 +/-0.17 MPa, the elastic modulus is 0.64 +/-0.09 MPa according to the stress-strain curve, and the tearing energy of the hydrogel heart valve is 15.77 +/-0.31 kJ/m2。
Example 8
The procedure was as described in example 7, except that a tubular hydrogel heart valve and heart were prepared, as shown in fig. 12 and 13.
Example 9
9.3750g of N-acryloyl semicarbazide and 3.125g of acrylamide were added to 37.5000g of a mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of dimethyl sulfoxide to water was 7: 3), 0.0625g of an initiator (LAP) (0.5% of the mass of the monomer) was added after the monomer was completely dissolved, 0.0125g of RAFT agent (4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid) (0.1% of the mass of the monomer) was added, and 0.0100g of lemon yellow was added to finally obtain a uniform and transparent photocurable hydrogel ink.
Printing and post-processing were the same as in example 7.
The mechanical properties of the hydrogel heart valve are tested by using a universal material testing machine, the test result is shown in figure 14, as can be seen from figure 14, when the strain is 405 +/-34%, the tensile strength reaches 2.42 +/-0.82 MPa, the elastic modulus is 1.12 +/-0.23 MPa according to the stress-strain curve calculation, and the tearing energy of the hydrogel heart valve is 23.04 +/-0.21 kJ/m2。
Example 10
The differences from example 7 are: no acrylamide was added.
The mechanical properties of the hydrogel heart valve are tested by using a universal material testing machine, the test result is shown in fig. 15, as can be seen from fig. 15, when the strain is 83 +/-25%, the tensile strength reaches 2.50 +/-0.28 MPa, and the elastic modulus is 33.40 +/-5.79 MPa calculated from a stress-strain curve. The tearing energy of the hydrogel heart valve is 15.28 +/-0.17 kJ/m2。
Example 11
The differences from example 7 are: the N-acryloyl semicarbazide is N-acryloyl glycinamide. The physical map is shown in FIG. 16.
Testing the mechanical property of the hydrogel heart valve by using a universal material testing machine, wherein the tensile strength of the hydrogel heart valve reaches 0.55 +/-0.06 MPa when the strain is 319 +/-12%; the elastic modulus is 0.13 plus or minus 0.09MPa and the tearing energy of the hydrogel heart valve is 3.55 plus or minus 0.43kJ/m calculated by a stress-strain curve2。
Comparative example 4
6.2500g of N-acryloyl semicarbazide and 6.2500g of acrylamide were added to 37.5000g of a mixed solvent of dimethyl sulfoxide and deionized water (the mass ratio of dimethyl sulfoxide to water was 7: 3), 0.0625g of an initiator (LAP) (0.5% of the mass of the monomer) was added after the monomer was completely dissolved, 0.0125g of RAFT reagent (4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid) (0.1% of the mass of the monomer) was added, and 0.0100g of lemon yellow was added to finally obtain a uniform and transparent photocurable hydrogel ink.
Printing and post-processing were the same as in example 7.
The mechanical properties of the hydrogel heart valve were tested by using a universal material testing machine, and the test results are shown in fig. 17, and it can be seen from fig. 17 that the tensile strength reached 14.62 ± 1.77kPa at a strain of 325% ± 73, and the elastic modulus was 6.11 ± 2.15kPa calculated from the stress-strain curve. The tearing energy of the hydrogel heart valve is 0.77 +/-0.01 kJ/m2。
Comparative example 5
The differences from example 7 are: no surface modification was performed.
The mechanical properties of the structured hydrogel heart valve are tested by using a universal material testing machine, the test result is shown in fig. 18, as can be seen from fig. 18, when the strain is 442 +/-45%, the tensile strength reaches 2.26 +/-0.10 MPa, the elastic modulus is 1.44 +/-0.17 MPa according to the stress-strain curve calculation, and the tearing energy of the structured hydrogel heart valve is 20.87 +/-0.66 kJ/m2。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A method of making a structured hydrogel, comprising the steps of:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model to obtain printed hydrogel;
water leaching the printed hydrogel to obtain the structured hydrogel;
the photo-curable hydrogel ink comprises the following components: monomers, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea;
the solvent includes water and dimethyl sulfoxide.
2. The method of claim 1, wherein the monomer further comprises a low density hydrogen bonding unsaturated monomer, and the low density hydrogen bonding unsaturated monomer comprises acrylamide or acrylic acid.
3. The method according to claim 1, wherein the mass ratio of water to dimethyl sulfoxide in the solvent is 9: 1-1: 9.
4. the method of claim 1, wherein the photoinitiator is an aqueous photoinitiator; the aqueous photoinitiator comprises one or more of a 2959 photoinitiator, a LAP photoinitiator, and a V-50 photoinitiator; the mass of the photoinitiator is 0.1-1% of the mass of the monomer.
5. The method according to any one of claims 1 to 4, wherein the content of the solute in the photocurable hydrogel ink is 5 to 30% by mass.
6. The method for preparing according to claim 1 or 4, wherein the parameters of the photocuring 3D printing include: the wavelength of the light source is 385-405 nm; the exposure time of each layer is 5 s-60 s; the thickness of the slicing layer is 0.05 mm-0.1 mm.
7. The method according to claim 1, wherein the water immersion is carried out for 5 to 15 days.
8. A preparation method of hydrogel heart and valve is characterized by comprising the following steps:
providing a photo-curable hydrogel ink;
carrying out photocuring 3D printing on the photocuring hydrogel ink according to a preset three-dimensional model of the heart and the valve to obtain printed hydrogel;
water leaching the printed hydrogel to obtain the structured hydrogel;
mixing the structured hydrogel and functional monomers, and carrying out surface modification to obtain the hydrogel heart and valve;
the photo-curable hydrogel ink comprises the following components: monomers, RAFT reagents, photoinitiators, dyes and solvents;
the monomer comprises a high-density hydrogen bond type unsaturated monomer, and the high-density hydrogen bond type unsaturated monomer comprises one or more of N-acryloyl semicarbazide, N-acryloyl glycinamide, allyl urea and allyl urea;
the solvent comprises water and dimethyl sulfoxide;
the functional monomer comprises sodium styrene sulfonate or a heparinoid type active monomer.
9. The method of claim 8, wherein the RAFT agent is a water-soluble RAFT agent; the water soluble RAFT agent comprises 4-cyano-4- (((ethylthio) thiocarbonyl) thio) pentanoic acid, 2- (n-butyl thiocarbonylthio) propanoic acid or 4-cyano-4- ((dodecylsulfanylthiocarbonyl) sulfanyl) pentanoic acid; the mass of the RAFT reagent is 0.1-2% of the mass of the monomer.
10. The preparation method according to claim 8, wherein the temperature of the surface modification is 60-90 ℃ and the time is 5 min-48 h.
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